Muscle weakness, injury and inflammation are important obstacles to normal function in individuals subjected to periods of muscle unloading followed by normal muscle use. These defects will acquire increased importance in health care for an aging population, in which convalescence can entail prolonged bedrest followed by attempts to regain normal ambulation. The design of preventative or therapeutic treatments to minimize muscle defects that arise upon reloading will rely upon identifying the factors that contribute to muscle injury, repair and growth. Our findings show that myeloid cells promote muscle injury and growth during reloading. We propose a model in which distinct populations of myeloid cells contribute to different phases of muscle adaptation to increased use. In our hypothesis, CD68+ macrophages target and remove cellular debris in advance of muscle repair and growth. These macrophages are classically-activated by Th1 cytokines, and then deactivated by interleukin-10 (IL-10). CD68+ cells are then replaced by two populations of alternatively-activated macrophages that promote muscle repair and growth. One population expresses the hemaglobin/haptoglobin receptor (CD163) and contributes to deactivation of the Th1 inflammatory response, and promotes muscle growth by the synthesis and release of leukemia inhibitory factor (LIF). The other population expresses the mannose receptor (CD206), participates in deactivating the Th1 response and promotes muscle healing. We will use mouse hindlimb suspension followed by reloading to induce muscle injury, repair and growth, and assess the effects of genetic modifications that perturb the expression of key molecules in our model. We will analyze the effects of the following manipulations on the repair and growth of muscle: 1) ablation of signaling by a cytokine necessary for classical activation of macrophages (IFN-gamma), 2) a macrophage-specific increase in expression of a cytokine that promotes growth (LIF), 3) null mutation of a cytokine necessary for deactivation of classically-activated macrophages (IL-10), and 4) a macrophage/neutrophil specific null mutation of a receptor that is necessary for alternative activation of macrophages (IL-4R alpha). This study will yield the first mechanistic findings concerning macrophage function in muscle repair and growth during increased loading.